The inflammatory cytokines IL-1 and TNF-.alpha. play an important role in a number of inflammatory diseases. (C. Dinarello et al., Inflammatory cytokines: Interleukin-1 and Tumor Necrosis Factor as Effector Molecules in Autoimmune Diseases, Curr. Opin. Immunol. 1991, 3, 941-48.) Rheumatoid arthritis is a prime example of such inflammatory diseases, and is thus the inflammatory disease focused on most in this section.
Rheumatoid arthritis is an inflammatory disease which affects millions of people and can affect any joint in the human body. Its symptoms range from mild pain and inflammation in affected joints, to severe and debilitating pain and inflammation. Although the disease is associated mainly with aging adults, it is not restricted to adults.
The most common rheumatoid arthritis therapy involves the use of nonsteroidal anti-inflammatory drugs (NSAID's) to alleviate symptoms. However, despite the widespread use of NSAID's, many individuals cannot tolerate the doses necessary to treat the disease over a prolonged period of time. In addition, NSAID's merely treat the symptoms of disease without affecting the underlying cause(s). Other drugs, such as methotrexate, gold salts, D-penicillamine and prednisone are often used when patients fail to respond to NSAID's. These drugs also have significant toxicities and their mechanisms of action remain unknown.
Receptor antagonists to IL-1 and monoclonal antibodies to TNF-.alpha. have been shown to reduce symptoms of rheumatoid arthritis in small-scale human clinical trials. (M. J. Elliot et al., Treatment of Rheumatoid Arthritis with Chimeric Monoclonal Antibodies to Tumor Necrosis Factor .alpha., Arthritis Rheum. 1993 36, 1681-90.)
In addition to protein-based therapies, there are small molecule agents which inhibit the production of these cytokines and have demonstrated activity in animal rheumatoid arthritis models. (J. C. Boehm et al., 1-Substituted 4-Aryl-5-pyridinylimidazoles: A New Class of Cytokine Suppressive Drugs with Low 5-Lipoxygenase and Cyclooxygenase Inhibitory Potency, J. Med. Chem., 1996, 39, 3929-37.) Of these small molecule agents, SB 203580 has proven effective in reducing the production of TNF-.alpha. and IL-1 in LPS-stimulated human monocyte cell lines with IC.sub.50 values of 50 to 100 nM. (J. Adams et al., Imidazole Derivatives And Their Use as Cytokine Inhibitor, International patent application WO 93/14081, 1993.) ##STR2##
In addition to this in vitro behavior, SB 203580 has been shown to inhibit the production of inflammatory cytokines in rats and mice at IC.sub.50 values of 15 to 25 mg/kg. (A. M. Badger, et al., Pharmacological Profile of SB 203580, A Selective Inhibitor of Cytokine Suppressive Binding Protein/p38 Kinase, in Animal Models of Arthritis, Bone Resorption, Endotoxin Shock and Immune Function, The Journal of Pharmacology and Experimental Therapeutics, 1996, 279, 1453-61.)
Due to SB 203580's oral activity and potency in animal models, researchers have suggested that a compound with this profile has potential as a viable treatment for rheumatoid arthritis. (A. M. Badger, et al. Pharmacological Profile of SB 203580, A Selective Inhibitor of Cytokine Suppressive Binding Protein/p38 Kinase, in Animal Models of Arthritis, Bone Resorption, Endotoxin Shock and Immune Function, The Journal of Pharmacology and Experimental Therapeutics, 1996, 279, 1453-61.)
SB 203580 and other small molecules reduce the production of inflammatory cytokines by inhibiting the activity of a serine/threonine kinase, p38 (also referred to in the art as "CSBP"), at an IC.sub.50 of 200 nM. (D. Griswold et al., Pharmacology of Cytokine Suppressive Anti-Inflammatory Drug Binding Protein (CSPB), A Novel Stress-Induced Kinase, Pharmacology Communications, 1996, 7, 323-29.) Although the precise mechanism of this kinase is unknown, it has been implicated in both the production of TNF-.alpha. and the signaling responses associated with the TNF-.alpha. receptor.
Rheumatoid arthritis, and the host of other inflammatory disorders, take a severe toll on those afflicted. There is thus a tremendous need for small molecule anti-inflammatory agents. To date, however, no such agent--including SB 203580--has ever been shown to be anti-inflammatory in human clinical trials.